Evidence from clinical studies of fetal alcohol spectrum disorders (FASD) has shown that prenatal ethanol exposure could lead to increased propensity of addiction. Results from animal studies also show prenatal ethanol exposure leads to behavioral phenotypes associated with increased addiction propensity and enhanced learning of drug cues. We have found prenatal ethanol exposure results in a persistent increase in glutamate synaptic transmission in dopamine (DA) neurons located in the ventral tegmental area (VTA), an effect thought to be a critical cellular mechanism for addiction. Specifically, we observe that prenatal ethanol exposure leads to a rectification of AMPA receptor-mediated current, suggesting an increased expression of high conductance GluR2 subunit-lacking AMPA receptors. We also observe a blockade of endocannabinoid (eCB)-mediated long-term depression (LTD). LTD plays a critical role in the weakening of synaptic strength. Both the blockade of LTD and increase in GluR2-lacking AMPA receptors observed in prenatal ethanol exposed animals are likely to contribute to a persistent increase in glutamate synaptic transmission in VTA DA neurons, which in turn leads to increased addiction propensity. In the proposed studies, we will use a multidisciplinary approach to further characterize the effects of prenatal ethanol exposure on increased glutamate synaptic transmission in VTA DA neurons. Specifically, we will seek to confirm whether prenatal ethanol exposure leads to an increased expression of GluR2-lacking AMPA receptors. We will also investigate the detailed mechanism leading to prenatal ethanol exposure- induced blockade of eCB-dependent LTD. Lastly, we will investigate if increased glutamate synaptic transmission caused by above two cellular mechanisms in VTA DA neurons indeed leads to increased addiction propensity in prenatal ethanol exposed animals. The results generated from the proposed studies will have important implications in the following areas. First, they will lead to a better understanding in the cellular/molecular mechanisms mediating prenatal ethanol exposure-induced increase in addiction propensity. The results, will provide important insights to better therapeutic strategies for behavioral problems of FASD. Second, the results will also help clarify the complex eCB signaling mechanisms within the mesolimbic/mesocortical DA systems. Although a critical role of eCB signaling in DA system function and addiction has been proposed, the detailed cellular mechanisms are not - characterized. The results from the proposed studies are likely to fill this gap. Third, the results may have broad impact beyond FASD. Other conditions leading to increased addiction propensity (e.g. psychostimulant or stress exposure) also alter DA system function, raising the possibility that a common brain mechanism mediates increased substance abuse propensity. The results from the proposed studies may provide insights to brain mechanisms mediating increased addiction propensity and the prevention of addiction in general. PUBLIC HEALTH RELEVANCE: Prenatal ethanol exposure leads to many adverse effects later in life which include increased risk of addiction. In the proposed studies, we will investigate if specific cellular changes in brain dopamine neurons are responsible for increased risk of addiction after prenatal ethanol exposure. The results will lead to better understanding in brain mechanisms mediating addictive behaviors and contribute to the development of preventive and treatment strategies for addiction in individuals with fetal alcohol spectrum disorders and other highly vulnerable individuals.